tbuckley/cabot-search huggingface dataset:
Aflibercept Monotherapy or Bevacizumab First for Diabetic Macular Edema
Authors: Chirag D. Jhaveri, Adam R. Glassman, Frederick L. Ferris, Danni Liu, Maureen G. Maguire, John B. Allen, Carl W. Baker, David Browning, Matthew A. Cunningham, Scott M. Friedman, Lee M. Jampol, Dennis M. Marcus, Daniel F. Martin, Carin M. Preston, Cynthia R. Stockdale, Jennifer K. Sun
Journal: New England Journal of Medicine (2022)

In eyes with diabetic macular edema, the relative efficacy of administering aflibercept monotherapy as compared with bevacizumab first with a switch to aflibercept if the eye condition does not improve sufficiently (a form of step therapy) is unclear.At 54 clinical sites, we randomly assigned eyes in adults who had diabetic macular edema involving the macular center and a visual-acuity letter score of 24 to 69 (on a scale from 0 to 100, with higher scores indicating better visual acuity; Snellen equivalent, 20/320 to 20/50) to receive either 2.0 mg of intravitreous aflibercept or 1.25 mg of intravitreous bevacizumab. The drug was administered at randomization and thereafter according to the prespecified retreatment protocol. Beginning at 12 weeks, eyes in the bevacizumab-first group were switched to aflibercept therapy if protocol-specified criteria were met. The primary outcome was the mean change in visual acuity over the 2-year trial period. Retinal central subfield thickness and visual acuity at 2 years and safety were also assessed.A total of 312 eyes (in 270 adults) underwent randomization; 158 eyes were assigned to receive aflibercept monotherapy and 154 to receive bevacizumab first. Over the 2-year period, 70% of the eyes in the bevacizumab-first group were switched to aflibercept therapy. The mean improvement in visual acuity was 15.0 letters in the aflibercept-monotherapy group and 14.0 letters in the bevacizumab-first group (adjusted difference, 0.8 letters; 95% confidence interval, -0.9 to 2.5; P = 0.37). At 2 years, the mean changes in visual acuity and retinal central subfield thickness were similar in the two groups. Serious adverse events (in 52% of the patients in the aflibercept-monotherapy group and in 36% of those in the bevacizumab-first group) and hospitalizations for adverse events (in 48% and 32%, respectively) were more common in the aflibercept-monotherapy group.In this trial of treatment of moderate vision loss due to diabetic macular edema involving the center of the macula, we found no evidence of a significant difference in visual outcomes over a 2-year period between aflibercept monotherapy and treatment with bevacizumab first with a switch to aflibercept in the case of suboptimal response. (Funded by the National Institutes of Health; Protocol AC ClinicalTrials.gov number, NCT03321513.).
Phenobarbital for Severe Alcohol Withdrawal Syndrome: A Multicenter Retrospective Cohort Study
Authors: Nicholas A. Bosch, Anica C. Law, Allan J. Walkey
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

"Phenobarbital for Severe Alcohol Withdrawal Syndrome: A Multicenter Retrospective Cohort Study." American Journal of Respiratory and Critical Care Medicine, 206(9), pp. 1171–1174
Sex Differences in the Progression of Metabolic Risk Factors in Diabetes Development
Authors: Yilin Yoshida, Zhipeng Chen, Robin L. Baudier, Marie Krousel-Wood, Amanda H. Anderson, Vivian A. Fonseca, Franck Mauvais-Jarvis
Journal: JAMA Network Open (2022)

This cohort study uses data from the Atherosclerosis Risk in Communities (ARIC) Study to investigate whether the increase in metabolic syndrome severity is more pronounced in women than men and whether the sex difference varies by race.
Hypertension and incident cardiovascular events after next-generation BTKi therapy initiation
Authors: Sunnia T. Chen, Leylah Azali, Lindsay Rosen, Qiuhong Zhao, Tracy Wiczer, Marilly Palettas, John Gambril, Onaopepo Kola-Kehinde, Patrick Ruz, Sujay Kalathoor, Kerry Rogers, Adam Kittai, Michael Grever, Farrukh Awan, John C. Byrd, Jennifer Woyach, Seema A. Bhat, Daniel Addison
Journal: Journal of Hematology & Oncology (2022)

Post-market analyses revealed unanticipated links between first-generation Bruton's tyrosine kinase inhibitor (BTKi) therapy, ibrutinib, and profound early hypertension. Yet, whether this is seen with novel selective second (next)-generation BTKi therapy, acalabrutinib, is unknown.Leveraging a large cohort of consecutive B cell cancer patients treated with acalabrutinib from 2014 to 2020, we assessed the incidence and ramifications of new or worsened hypertension [systolic blood pressure (SBP) ≥ 130 mmHg] after acalabrutinib initiation. Secondary endpoints were major cardiovascular events (MACE: arrhythmias, myocardial infarction, stroke, heart failure, cardiac death) and disease progression. Observed incident hypertension rates were compared to Framingham heart-predicted and ibrutinib-related rates. Multivariable regression and survival analysis were used to define factors associated with new/worsened hypertension and MACE, and the relationship between early SBP increase and MACE risk. Further, the effect of standard antihypertensive classes on the prevention of acalabrutinib-related hypertension was assessed.Overall, from 280 acalabrutinib-treated patients, 48.9% developed new/worsened hypertension over a median of 41 months. The cumulative incidence of new hypertension by 1 year was 53.9%, including 1.7% with high-grade (≥ 3) hypertension. Applying the JNC 8 cutoff BP of ≥ 140/90 mmHg, the observed new hypertension rate was 20.5% at 1 year, > eightfold higher than the Framingham-predicted rate of 2.4% (RR 8.5, P < 0.001), yet 34.1% lower than ibrutinib (12.9 observed-to-expected ratio, P < 0.001). In multivariable regression, prior arrhythmias and Black ancestry were associated with new hypertension (HR 1.63, HR 4.35, P < 0.05). The degree of SBP rise within 1 year of treatment initiation predicted MACE risk (42% HR increase for each + 5 mmHg SBP rise, P < 0.001). No single antihypertensive class prevented worsened acalabrutinib-related hypertension.Collectively, these data suggest that hypertension may be a class effect of BTKi therapies and precedes major cardiotoxic events.
Overall Survival Results From the POLO Trial: A Phase III Study of Active Maintenance Olaparib Versus Placebo for Germline BRCA-Mutated Metastatic Pancreatic Cancer
Authors: Hedy L. Kindler, Pascal Hammel, Michele Reni, Eric Van Cutsem, Teresa Macarulla, Michael J. Hall, Joon Oh Park, Daniel Hochhauser, Dirk Arnold, Do-Youn Oh, Anke Reinacher-Schick, Giampaolo Tortora, Hana Algül, Eileen M. O'Reilly, Sonal Bordia, David McGuinness, Karen Cui, Gershon Y. Locker, Talia Golan
Journal: Journal of Clinical Oncology (2022)

The phase III POLO study demonstrated significant progression-free survival (PFS) benefit for active olaparib maintenance therapy versus placebo for patients with metastatic pancreatic adenocarcinoma and a germline BRCA mutation. Here, we report the final analysis of overall survival (OS) and other secondary end points.
Development and Validation of an Artificial Intelligence Model for Small Bowel Capsule Endoscopy Video Review
Authors: Xia Xie, Yu-Feng Xiao, Xiao-Yan Zhao, Jian-Jun Li, Qiang-Qiang Yang, Xue Peng, Xu-Biao Nie, Jian-Yun Zhou, Yong-Bing Zhao, Huan Yang, Xi Liu, En Liu, Yu-Yang Chen, Yuan-Yuan Zhou, Chao-Qiang Fan, Jian-Ying Bai, Hui Lin, Anastasios Koulaouzidis, Shi-Ming Yang
Journal: JAMA Network Open (2022)

Reading small bowel capsule endoscopy (SBCE) videos is a tedious task for clinicians, and a new method should be applied to solve the situation.To develop and evaluate the performance of a convolutional neural network algorithm for SBCE video review in real-life clinical care.In this multicenter, retrospective diagnostic study, a deep learning neural network (SmartScan) was trained and validated for the SBCE video review. A total of 2927 SBCE examinations from 29 medical centers were used to train SmartScan to detect 17 types of CE structured terminology (CEST) findings from January 1, 2019, to June 30, 2020. SmartScan was later validated with conventional reading (CR) and SmartScan-assisted reading (SSAR) in 2898 SBCE examinations collected from 22 medical centers. Data analysis was performed from January 25 to December 31, 2021.An artificial intelligence-based tool for interpreting clinical images of SBCE.The detection rate and efficiency of CEST findings detected by SSAR and CR were compared.A total of 5825 SBCE examinations were retrospectively collected; 2898 examinations (1765 male participants [60.9%]; mean [SD] age, 49.8 [15.5] years) were included in the validation phase. From a total of 6084 CEST-classified SB findings, SSAR detected 5834 findings (95.9%; 95% CI, 95.4%-96.4%), significantly higher than CR, which detected 4630 findings (76.1%; 95% CI, 75.0%-77.2%). SmartScan-assisted reading achieved a higher per-patient detection rate (79.3% [2298 of 2898]) for CEST findings compared with CR (70.7% [2048 of 2298]; 95% CI, 69.0%-72.3%). With SSAR, the mean (SD) number of images (per SBCE video) requiring review was reduced to 779.2 (337.2) compared with 27 910.8 (12 882.9) with CR, for a mean (SD) reduction rate of 96.1% (4.3%). The mean (SD) reading time with SSAR was shortened to 5.4 (1.5) minutes compared with CR (51.4 [11.6] minutes), for a mean (SD) reduction rate of 89.3% (3.1%).This study suggests that a convolutional neural network-based algorithm is associated with an increased detection rate of SBCE findings and reduced SBCE video reading time.
Mediterranean Diet and Brain Health in Hispanic or Latino Adults
Authors: Farzaneh A. Sorond
Journal: JAMA Network Open (2022)

Bayan Moustafa, DO; Gabriela Trifan, MD; Carmen R. Isasi, MD, PhD; Richard B. Lipton, MD; Daniela Sotres-Alvarez, DrPH; Jianwen Cai, PhD; Wassim Tarraf, MBA, PhD; Ariana Stickel, PhD; Josiemer Mattei, MPH, PhD; Gregory A. Talavera, MD, MPH; Martha L. Daviglus, MD, PhD; Hector M. González, PhD; Fernando D. Testai, MD, PhD
Genetic Risk of Second Primary Cancer in Breast Cancer Survivors: The Multiethnic Cohort Study
Authors: Fei Chen, Sungshim L. Park, Lynne R. Wilkens, Peggy Wan, Steven N. Hart, Chunling Hu, Siddhartha Yadav, Fergus J. Couch, David V. Conti, Adam J. de Smith, Christopher A. Haiman
Journal: Cancer Research (2022)

Abstract Women who have had breast cancer in the past are at increased risk of developing a second primary cancer (SPC), including second primary breast cancer (SPBC) or a second primary non-breast cancer (SPNBC). In the Multiethnic Cohort (MEC) Study, we conducted a prospective cohort analysis in 3,223 female breast cancer survivors from five racial/ethnic populations (White, African American, Japanese American, Latino, and Native Hawaiian) to assess the association of rare pathogenic variants (PV) in 37 known cancer predisposition genes with risk of SPC. A total of 719 (22.3%) women developed SPC, of which, 323 (10.0%) were SPBC. Germline PVs in BRCA1 (HR, 2.28; 95% CI, 1.11–4.65) and ERCC2 (HR, 3.51; 95% CI, 1.29–9.54) were significantly enriched in women with SPC. In the subtype analysis for SPBC, a significant association of ERCC2 PVs (HR, 5.09; 95% CI, 1.58–16.4) and a suggestive association of BRCA2 PVs (HR, 2.24; 95% CI, 0.91–5.55) were observed. There was also a higher risk of SPNBC in carriers of BRCA1 PVs (HR, 2.98; 95% CI, 1.21–7.36). These results provide evidence that germline PVs in BRCA1, BRCA2, and ERCC2 contribute to the development of SPC in breast cancer survivors. These findings also suggest that compromised DNA repair mechanisms could be a predisposition factor for SPC in patients with breast cancer, supporting the need for closer monitoring of SPC in women carrying PVs in these genes. Significance: This multiethnic study links germline pathogenic variants in BRCA1, BRCA2, and ERCC2 to the development of second primary cancer in breast cancer survivors, providing biological insights and biomarkers to guide patient monitoring.
Role of Patient-Reported Outcome Measures in the Inpatient Setting—Reply
Authors: Ryan D. Nipp, Areej El-Jawahri, Jennifer S. Temel
Journal: JAMA Oncology (2022)

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Expert consensus on early childhood caries management
Authors: Jing Zou, Qin Du, Lihong Ge, Jun Wang, Xiaojing Wang, Yuqing Li, Guangtai Song, Wei Zhao, Xu Chen, Beizhan Jiang, Yufeng Mei, Yang Huang, Shuli Deng, Hongmei Zhang, Yanhong Li, Xuedong Zhou
Journal: International Journal of Oral Science (2022)

Early childhood caries (ECC) is a significant chronic disease of childhood and a rising public health burden worldwide. ECC may cause a higher risk of new caries lesions in both primary and permanent dentition, affecting lifelong oral health. The occurrence of ECC has been closely related to the core microbiome change in the oral cavity, which may be influenced by diet habits, oral health management, fluoride use, and dental manipulations. So, it is essential to improve parental oral health and awareness of health care, to establish a dental home at the early stage of childhood, and make an individualized caries management plan. Dental interventions according to the minimally invasive concept should be carried out to treat dental caries. This expert consensus mainly discusses the etiology of ECC, caries-risk assessment of children, prevention and treatment plan of ECC, aiming to achieve lifelong oral health.
Pathogenic autoantibodies to IFN-γ act through the impedance of receptor assembly and Fc-mediated response
Authors: Han-Po Shih, Jing-Ya Ding, Junel Sotolongo Bellón, Yu-Fang Lo, Pei-Han Chung, He-Ting Ting, Jhan-Jie Peng, Tsai-Yi Wu, Chia-Hao Lin, Chia-Chi Lo, You-Ning Lin, Chun-Fu Yeh, Jiun-Bo Chen, Ting-Shu Wu, Yuag-Meng Liu, Chen-Yen Kuo, Shang-Yu Wang, Kun-Hua Tu, Chau Yee Ng, Wei-Te Lei, Yu-Huan Tsai, Jou-Han Chen, Ya-Ting Chuang, Jing-Yi Huang, Félix A. Rey, Hung-Kai Chen, Tse-Wen Chang, Jacob Piehler, Chih-Yu Chi, Cheng-Lung Ku
Journal: The Journal of Experimental Medicine (2022)

Anti-interferon (IFN)–γ autoantibodies (AIGAs) are a pathogenic factor in late-onset immunodeficiency with disseminated mycobacterial and other opportunistic infections. AIGAs block IFN-γ function, but their effects on IFN-γ signaling are unknown. Using a single-cell capture method, we isolated 19 IFN-γ–reactive monoclonal antibodies (mAbs) from patients with AIGAs. All displayed high-affinity (KD &amp;lt; 10−9 M) binding to IFN-γ, but only eight neutralized IFN-γ–STAT1 signaling and HLA-DR expression. Signal blockade and binding affinity were correlated and attributed to somatic hypermutations. Cross-competition assays identified three nonoverlapping binding sites (I–III) for AIGAs on IFN-γ. We found that site I mAb neutralized IFN-γ by blocking its binding to IFN-γR1. Site II and III mAbs bound the receptor-bound IFN-γ on the cell surface, abolishing IFN-γR1–IFN-γR2 heterodimerization and preventing downstream signaling. Site III mAbs mediated antibody-dependent cellular cytotoxicity, probably through antibody–IFN-γ complexes on cells. Pathogenic AIGAs underlie mycobacterial infections by the dual blockade of IFN-γ signaling and by eliminating IFN-γ–responsive cells.
Genome-wide analyses of 200,453 individuals yield new insights into the causes and consequences of clonal hematopoiesis
Authors: Siddhartha P. Kar, Pedro M. Quiros, Muxin Gu, Tao Jiang, Jonathan Mitchell, Ryan Langdon, Vivek Iyer, Clea Barcena, M. S. Vijayabaskar, Margarete A. Fabre, Paul Carter, Slavé Petrovski, Stephen Burgess, George S. Vassiliou
Journal: Nature Genetics (2022)

Abstract Clonal hematopoiesis (CH), the clonal expansion of a blood stem cell and its progeny driven by somatic driver mutations, affects over a third of people, yet remains poorly understood. Here we analyze genetic data from 200,453 UK Biobank participants to map the landscape of inherited predisposition to CH, increasing the number of germline associations with CH in European-ancestry populations from 4 to 14. Genes at new loci implicate DNA damage repair ( PARP1 , ATM , CHEK2 ), hematopoietic stem cell migration/homing ( CD164 ) and myeloid oncogenesis ( SETBP1 ). Several associations were CH-subtype-specific including variants at TCL1A and CD164 that had opposite associations with DNMT3A - versus TET2 -mutant CH, the two most common CH subtypes, proposing key roles for these two loci in CH development. Mendelian randomization analyses showed that smoking and longer leukocyte telomere length are causal risk factors for CH and that genetic predisposition to CH increases risks of myeloproliferative neoplasia, nonhematological malignancies, atrial fibrillation and blood epigenetic ageing.
A paper-based assay for the colorimetric detection of SARS-CoV-2 variants at single-nucleotide resolution
Authors: Ting Zhang, Ruijie Deng, Yuxi Wang, Chengyong Wu, Kaixiang Zhang, Chunyan Wang, Ningqiang Gong, Rodrigo Ledesma-Amaro, Xucong Teng, Chunrong Yang, Ting Xue, Yong Zhang, Yun Hu, Qiang He, Weimin Li, Jinghong Li
Journal: Nature Biomedical Engineering (2022)
A Phase I Trial of TB-403 in Relapsed Medulloblastoma, Neuroblastoma, Ewing Sarcoma, and Alveolar Rhabdomyosarcoma
Authors: Giselle Saulnier-Sholler, Dan G. Duda, Genevieve Bergendahl, David Ebb, Matija Snuderl, Theodore W. Laetsch, Jennifer Michlitsch, Derek Hanson, Michael S. Isakoff, Kevin Bielamowicz, Jacqueline M. Kraveka, William Ferguson, Peter Carmeliet, A. De Deene, Lore Gijsen, Rakesh K. Jain
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Placental growth factor (PlGF) and its receptor neuropilin 1 are elevated in malignant embryonal tumors and mediate tumor progression by promoting cell proliferation, survival, and metastasis. TB-403 is a blocking monoclonal antibody against PlGF that inhibits tumor growth and increases survival in orthotopic medulloblastoma models. Patients and Methods: We conducted a phase I, open-label, multicenter, dose-escalation study of TB-403 in pediatric subjects with relapsed or refractory cancers. The study involved four dose levels (20 mg/kg, 50 mg/kg, 100 mg/kg, 175 mg/kg) using a 3 + 3 dose-escalation scheme. Subjects received two doses of TB-403 (days 1 and 15) per cycle. After cycle 1, temozolomide or etoposide could be added. The primary objective was to determine the maximum tolerated dose (MTD) of TB-403 monotherapy during a dose-limiting toxicity assessment period. The secondary and exploratory objectives included efficacy, drug pharmacokinetics, and detection of pharmacodynamic biomarkers. Results: Fifteen subjects were treated in four dose levels. All subjects received two doses of TB-403 in cycle 1. Five serious treatment-emergent adverse events were reported in 3 subjects, but MTD was not reached. While no complete nor partial responses were observed, 7 of 11 relapsed subjects with medulloblastoma experienced stable disease, which persisted for more than 100 days in 4 of 7 subjects. Conclusions: TB-403 was safe and well tolerated at all dose levels. No MTD was reached. The results look encouraging and therefore warrant further evaluation of efficacy in pediatric subjects with medulloblastoma.
Error in Table
Journal: JAMA Network Open (2022)

Christopher L. Mosher, MD, MHS; Michael G. Nanna, MD, MHS; Oliver K. Jawitz, MD, MHS; Vignesh Raman, MD, MHS; Norma E. Farrow, MD, MHS; Samia Aleem, MBBS, MHS; Richard Casaburi, MD, PhD; Neil R. MacIntyre, MD; Scott M. Palmer, MD, MHS; Evan R. Myers, MD, MPH
Multiscale optical and optoacoustic imaging of amyloid-β deposits in mice
Authors: Ruiqing Ni, Zhenyue Chen, Xosé Luís Deán-Ben, Fabian F. Voigt, Daniel Kirschenbaum, Gloria Shi, Alessia Villois, Quanyu Zhou, Alessandro Crimi, Paolo Arosio, Roger M. Nitsch, K. Peter R. Nilsson, Adriano Aguzzi, Fritjof Helmchen, Jan Klohs, Daniel Razansky
Journal: Nature Biomedical Engineering (2022)
Long covid and apheresis: a miracle cure sold on a hypothesis of hope
Authors: Kamran Abbasi
Journal: BMJ (2022)

The case history is presented of a patient with cystic fibrosis in whom the treatment of allergic bronchopulmonary aspergillosis with itraconazole produced an initial response but was complicated by profound adrenal shutdown and impairment of inhaled steroid clearance resulting in paradoxical Cushing’s syndrome. The authors conclude that, while it is laudable to attempt to reduce the steroid burden in any patient, it is imperative that due vigilance is exercised when using a combination of agents which interact. If such a combination therapy is embarked upon, regular assessment of the pituitary adrenal axis is advisable.
Mapping the Immune Landscape in Metastatic Melanoma Reveals Localized Cell–Cell Interactions That Predict Immunotherapy Response
Authors: Asier Antoranz, Yannick Van Herck, Maddalena M. Bolognesi, Seodhna M. Lynch, Arman Rahman, William M. Gallagher, Veerle Boecxstaens, Jean-Christophe Marine, Giorgio Cattoretti, Joost J. van den Oord, Frederik De Smet, Oliver Bechter, Francesca M. Bosisio
Journal: Cancer Research (2022)

Abstract While immune checkpoint–based immunotherapy (ICI) shows promising clinical results in patients with cancer, only a subset of patients responds favorably. Response to ICI is dictated by complex networks of cellular interactions between malignant and nonmalignant cells. Although insights into the mechanisms that modulate the pivotal antitumoral activity of cytotoxic T cells (Tcy) have recently been gained, much of what has been learned is based on single-cell analyses of dissociated tumor samples, resulting in a lack of critical information about the spatial distribution of relevant cell types. Here, we used multiplexed IHC to spatially characterize the immune landscape of metastatic melanoma from responders and nonresponders to ICI. Such high-dimensional pathology maps showed that Tcy gradually evolve toward an exhausted phenotype as they approach and infiltrate the tumor. Moreover, a key cellular interaction network functionally linked Tcy and PD-L1+ macrophages. Mapping the respective spatial distributions of these two cell populations predicted response to anti-PD-1 immunotherapy with high confidence. These results suggest that baseline measurements of the spatial context should be integrated in the design of predictive biomarkers to identify patients likely to benefit from ICI. Significance: This study shows that spatial characterization can address the challenge of finding efficient biomarkers, revealing that localization of macrophages and T cells in melanoma predicts patient response to ICI. See related commentary by Smalley and Smalley, p. 3198